Read-Only Case Details Reviewed: Mar 2009

JPC SYSTEMIC PATHOLOGY

URINARY SYSTEM

January 2024

U-V06

Signalment (JPC # 1917806): 8-month-old female spayed domestic shorthair cat.

HISTORY: This kitten presented for progressive neurologic symptoms and an inability to walk. Despite medical therapy, the kitten continued to decline, became anorexic and icteric and was unable to stand. Euthanasia was elected. The prosector noted multifocal raised white nodules (up to 3 mm) on the serosal surfaces and parenchyma of the kidneys, liver and lungs. The nodules appeared vasocentric within the kidney.

HISTOPATHOLOGIC DESCRIPTION: Kidney: Affecting 40% of this section of kidney, to include all levels (renal pelvis to capsule), multifocal small and medium caliber venules are obscured or disrupted by numerous macrophages and neutrophils with fewer lymphocytes and plasma cells admixed with cellular and karyorrhectic debris (necrotizing phlebitis), eosinophilic hyalinized material (fibrin; fibrinoid necrosis) and contain intraluminal polymerized fibrin with entrapped debris (fibrin thrombi); less affected venules are lined by hypertrophied (reactive) endothelial cells and surrounded by previously described inflammation. The inflammatory infiltrate extends into the surrounding parenchyma, separating and replacing normal renal parenchyma, and is admixed with plump fibroblasts, fibrous connective tissue, perpendicularly oriented small caliber vessels (granulation tissue), fibrin, hemorrhage, edema, and large irregular foci with loss of differential staining (coagulative necrosis). In affected areas, remaining tubules are characterized by one or more of the following changes: ectatic, lined by attenuated epithelium and containing intraluminal eosinophilic proteinaceous material mixed with few sloughed cells or necrotic debris, swollen with finely vacuolated cytoplasm (degeneration), shrunken with hypereosinophilic cytoplasm and pyknotic nucleus (necrotic), piled up with mitotic figures and increased basophilia (regeneration), contain one to few large discrete intracytoplasmic vacuoles (lipidosis), or rarely within the medulla are replaced by deeply basophilic fragmented material (mineral). Remaining glomeruli within affected areas often have a shrunken glomerular tuft (atrophy) with dilation of the uriniferous space with proteinaceous material. The renal pelvis urothelium is multifocally hyperplastic with short papillary fronds, vacuolated (degenerate), individually shrunken and hypereosinophilic (single cell necrosis) and/or contains low numbers of previously described transmigrating inflammatory cells and hemorrhage.

MORPHOLOGIC DIAGNOSIS: Kidney: Phlebitis, interstitial nephritis, and capsulitis, pyogranulomatous and necrotizing, multifocal to coalescing, marked with fibrin thrombi, and tubular and glomerular loss, domestic shorthair, feline.

ETIOLOGIC DIAGNOSIS: Coronaviral nephritis

CAUSE: Mutated feline enteric coronavirus (feline infectious peritonitis virus)

GENERAL DISCUSSION:

Feline coronavirus (FCoV; enveloped RNA virus; Family Coronaviridae, genus Alphacoronavirus, species Aphacoronavirus-1) is ubiquitous and has:
1. Two biologic pathotypes: Feline enteric coronavirus (FECV) and Feline infectious peritonitis virus (FIPV)
2. Two antigenically distinct serotypes (I and II); serotype I stimulates higher antibody titers and is more frequently associated with FIPV
3. Wide range of virulence (asymptomatic carrier, enteric disease, and fatal virulent systemic infection)
Common cause of feline mortality, accounting for up to 12% of deaths
Primarily affects domestic cats, but can cause disease in wild felids (e.g. cheetahs)

PATHOGENESIS:

FECV: Fecal-oral transmission or contact with carrier saliva or respiratory droplets (e.g. from grooming, contaminated bowls) > infects terminally differentiated cecal and colonic enterocytes > either cleared or asymptomatic persistent infection (within an unidentified mucosal [stem] cell) with viral shedding; some cats may develop catarrhal to hemorrhagic enteritis with mild villar blunting and fusion
FIPV: Within individual cats, FECV spike mutates (complex process, involving several genes and proteins), gaining ability to replicate in macrophages/monocytes and loses tropism for enterocytes > FIPV spreads into lamina propria and then macrophages in Peyer’s patches (unknown mechanism) > macrophage-associated trafficking to regional lymph nodes > systemic dissemination > either cleared or develops a continuum of disease (effusive [wet] or non-effusive [dry] forms; often a combination of both) with hallmark vasculitis/perivasculitis and pyogranulomatous inflammation
1. FECV mutates more rapidly (10-100 fold) in cats with FIV, however the incidence is not higher in cats with FIV or FeLV
2. Use spike proteins (S1, S2) and glycoproteins (M, E) to bind feline aminopeptidase-N on monocytes and macrophages
3. Each FIPV is unique to an individual cat and not transmissible; however disease may “cluster” in households
4. Virus-infected macrophages target small to medium-sized veins - mechanism of injury is chronic-active pyogranulomatous inflammation
Progression of FIP depends on the cats’ immune response:
1. Strong cell-mediated response – Clears virus; do not develop FIP
2. Weak cell-mediated response – Dry (noneffusive) form; type IV hypersensitivity with CD4+ cell heavy vasocentric granulomatous inflammation
3. No cell-mediated response – Wet (effusive) form; an effective humoral response worsens the disease; antigen-antibody complexes deposit in venules (type III hypersensitivity) > complement activation, neutrophil chemotaxis, macrophages activation, pro-inflammatory cytokine release > vasculitis, increased permeability > fibrinous effusions and polyserositis; rapid clinical course
Role of inflammatory mediators:
1. Low TNF-a/high INF-y favors clearing FIPV
2. High TNF-a/low INF-y favors disease
3. A recent paper (Malbon et al, J Comp Path 2019) found that the mesenteric lymph nodes of FIP cats had higher expression of toll-like receptors 2, 4, and 9, inflammatory cytokines/chemokines (IL-1B, IL-6, IL-15, TNF-a, CXCL10, CCL8, INF-a, IFN-B, IFN-y), and transcription factors STAT1 and STAT2; this suggests an inflammatory response to viral structural proteins and nucleic acids

TYPICAL CLINICAL FINDINGS:

Predilection for young, intact, purebred male cats
Effusive (wet) form - Severe abdominal distension with high protein effusion (up to 1L; thick, viscous, typically clear, yellow fluid +/- flocculant fibrin strands), wasting (from protein loss), dyspnea (from pleural effusion), cardiac tamponade (rare), ocular/CNS signs (rare), lameness, acute death; rapid clinical course - die within a few weeks or rarely recover after passing through a noneffusive phase
Noneffusive (dry) form - Insidious onset with signs related to the most severely affected organs; ocular disease, nervous signs (ataxia, paraparesis, head tilt, specific nerve palsies, nystagmus, behavioral changes, dullness, coma, seizures), hepatic or pancreatic insufficiency, diarrhea; ocular or nervous signs may present without systemic signs

TYPICAL GROSS FINDINGS:

Effusive (wet) form – Fibrinous polyserositis with effusive peritonitis/pleuritis
1. Serosal surfaces (peritoneum > pleura) covered by granular fibrin with adhesions between organs and body wall
2. Thickened mesentery, contracted omentum, and 1-3mm foci of necrosis, raised plaques, and nodular cellular infiltrations tracking vessels on organs
3. Lungs dark and rubbery
4. +/- generalized synovitis
Noneffusive (dry) form – Multifocal, multisystemic vasocentric pyogranulomatous inflammation
1. Peritonitis and/or pleuritis with multifocal random, white-pale gray, variably sized vasocentric granulomatous nodules, especially on kidneys, liver, pancreas, testicular tunica vaginalis
2. Gastrointestinal tract, esp large intestine – Marked thickening by nodular, firm white exudate in large intestine with adhesion to adjacent enlarged lymph nodes
3. Lymph nodes – Lymphadenopathy
4. Eyes – Diffuse uveitis, chorioretinitis, and/or panophthalmitis with fibrin in anterior chamber and vitreous; keratic precipitates; most cats who die of disease have ocular involvement
  - In a recent paper (Wronski et al, Vet Pathol 2023), only 40% of the FIP cases had macroscopic gross changes, but all cases had histologic ocular disease regardless of effusive or noneffusive form; main lesion of neutrophilic and histocytic panuveitis +/- meningitis of optic nerve and fibrin within the ocular chamber
5. CNS – Subtle granulomatous plaques in leptomeninges, brain, and/or spinal cord, fibrin-rich gelatinous exudate in ventricles +/- hydromyelia, hydrocephalus, syringomyelia from obstruction of CSF, cerebellar herniation
6. Skin – Rare; multifocal, nonpruritic, erythematous cutaneous papules to nodules

TYPICAL LIGHT MICROSCOPIC FINDINGS:

Hallmark = Generalized vasculitis and perivasculitis, esp small to medium sized venules of leptomeninges, renal cortex, eyes, occasionally lungs, liver, others
1. Wet and dry forms of FIP are identical histologically – Pyogranulomatous phlebitis with predominantly macrophages and fewer lymphocytes, plasma cells, and neutrophils
2. +/- Vascular necrosis, narrowed lumens, thrombosis, infarction, and adventitial fibrosis
Omentum, mesentery, serosa - Mesothelial hyperplasia, fibrinosuppurative to pyogranulomatous serositis
Kidneys – Severe multifocal lymphoplasmacytic interstitial nephritis
Gut – Extension from vasculitis/serosa; can be transmural and result in segmental infarction
Lymph nodes – Pyogranulomatous lymphadenitis, which may replace whole node
CNS – Pyogranulomatous vasculitis with prominent involvement of periventricular white matter and choroid plexus; epdendymal syncytia; parenchymal or meningeal necrosis
Eyes – Anterior to pan-uveitis (mixed inflammation), worst in ciliary body and adjacent limbic sclera; lymphoplasmacytic perivasculitis in retrobulbar connective tissue, optic nerve sheath, and retina +/- retinal detachment; globular accumulations of macs/neutrophils adhered to corneal endothelium (keratic precipitates)
Lungs – Interstitial (pyogranulomatous) pneumonia with pulmonary vasculitis
Skin – Multifocal pyogranulomatous perivascular to nodular dermatitis +/- vasculitis

ADDITIONAL DIAGNOSTIC TESTS:

Clinical signs with gross and histologic findings often diagnostic
IHC (tissue) or PCR (serum, effusion) – Gold standard
1. A recent study (Sangl et al, JDVI 2020) found RT-rtPCR of aqueous humor for FCoV RNA had a 100% specificity and 35.5% sensitivity; may be helpful for antemortem diagnosis of FIP
Supportive diagnostics:
1. Fluid analysis – Cavitary effusion is odorless, straw colored, viscous +/- flecks or strands; foams when agitated (high protein content); protein >4 g/dL; cellularity variable, but usually 2000-6000 cells/uL
2. Cytology:
  - Cavitary effusion – Pink stippled to granular background with protein crescents, fibrin and low to moderate cellularity (degenerate lymphocytes, macrophages, mesothelial cells, neutrophils)
  - CSF – Variable; neutrophilic > mononuclear pleocytosis and elevated protein concentration
  - Renal aspirates – Highly cellular with pyogranulomatous inflammation
  - Synovial fluid – Moderate increased mononuclear cellularity
3. FCoV antibody titers - >1:1600 suggestive of FIP
4. Acidic fixatives in aqueous humor – Coagulation indicates increased protein (suggestive of FIP)
5. CBC - Leukocytosis with neutrophilia
6. Chemistry panel – Hypergammaglobulinemia and elevated ALT common
7. Albumin-to-globulin ratio – Serum AG ratio <0.8 g/dL and effusion AG ratio <0.9 g/dL suggestive of FIP
8. Protein electrophoresis of effusions – Similar pattern between effusion and serum
9. MRI – Abnormalities involving the ventricular lining and meninges suggestive
Unhelpful diagnostics:
1. Anti-FCoV antibody serology (ELISA, IF) – Interpret with caution; may cross react with “normal” FECV, which most cats have; 10% of FIP positive cats are negative
2. Immunocytochemistry
  - Mesenteric lymph node aspirates - A recent study (Felten et al, JDVI 2019) found that this only correctly identified FIP cases 50% of the time
  - Aqueous humor aspirate – A recent study (Sangl et al, JDVI 2020) found this to be unreliable for the diagnosis of FIP (sensitivity 62.5%, specificity 80%)

DIFFERENTIAL DIAGNOSIS:

Effusive form: Bacterial peritonitis, chylothorax, pyothorax, cancers associated with effusion, heart failure or cirrhosis of the liver with abdominal transudate
Non-effusive form: Lymphoma, steatitis, mycotic infections, toxoplasmosis

COMPARATIVE PATHOLOGY:

Bovine coronavirus (winter dysentery)	Bovine	Gastroenteritis, coronavirus implicated
Canine enteric coronavirus (D-V03)	Canine	Enteritis
Canine respiratory coronavirus	Canine	Respiratory disease
Feline infectious peritonitis virus (P-V15; N-V17; S-V03)	Feline	Peritonitis, pneumonia, meningoencephalitis, panophthalmitis; granulomatous vasculitis
Feline enteric coronavirus	Feline	Diarrhea in kittens; mild villous atrophy
Mouse hepatitis virus (D-V04)	Mouse	Polytropic strains: Hepatic necrosis, enteritis, encephalomyelitis; syncytia formation
Porcine transmissible gastroenteritis (D-V06)	Porcine	Gastroenteritis
Porcine hemagglutinating encephalomyelitis virus	Porcine	Vomiting, wasting, and encephalomyelitis (usually no diarrhea)
Porcine epidemic diarrhea	Porcine	Gastroenteritis (western Europe, similar to TGE)
Rat coronavirus	Rat	Rhinitis, tracheitis, pneumonitis in young
Sialodacryoadenitis virus (D-V05; S-V02)	Rat	Sialodacryoadenitis, porphyrin released from damaged harderian gland, squamous metaplasia of ducts
Avian infectious bronchitis	Chickens	Tracheobronchitis, nephritis, wrinkled eggs
Bluecomb (turkeys)	Turkeys	Enteritis, cyanosis of the comb
Rabbit coronavirus	Rabbits	Enteritis, myocarditis
SARS-CoV-1	Humans	Severe Acute Respiratory Syndrome (civet – source/amplification host)
SARS-CoV-2	Humans/Mink	Coronavirus Disease 2019
MERS-CoV	Humans	Middle Eastern Respiratory Syndrome (camels – reservoir host)
Epizootic catarrhal enteritis (ECE)	Ferrets	Profuse, green mucoid diarrhea in adults
Systemic Coronavirus-Associated Disease	Ferrets	Pyogranulomatous inflammation similar to FIP within numerous organs and pancytopenia

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